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EP1437352A1 - Compose de benzymidazole, procede de production et d'utilisation de celui-ci - Google Patents

Compose de benzymidazole, procede de production et d'utilisation de celui-ci Download PDF

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Publication number
EP1437352A1
EP1437352A1 EP02768002A EP02768002A EP1437352A1 EP 1437352 A1 EP1437352 A1 EP 1437352A1 EP 02768002 A EP02768002 A EP 02768002A EP 02768002 A EP02768002 A EP 02768002A EP 1437352 A1 EP1437352 A1 EP 1437352A1
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EP
European Patent Office
Prior art keywords
group
compound
halogen
methyl
substituent
Prior art date
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EP02768002A
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German (de)
English (en)
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EP1437352A4 (fr
Inventor
Keiji Kamiyama
Fumihiko Sato
Hiroshi Banno
Atsushi Hasuoka
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Publication of EP1437352A1 publication Critical patent/EP1437352A1/fr
Publication of EP1437352A4 publication Critical patent/EP1437352A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to a benzimidazole compound, which is converted to a proton pump inhibitor in living organisms and shows an anti-ulcer activity and the like, a production method thereof and use thereof.
  • a proton pump inhibitor, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole, and a salt thereof having an anti-ulcer activity are reported in JP-A-61-50978 and the like.
  • the present inventors have first synthesized a compound represented by the following formula (I) and first found that this compound has unexpectedly superior stability to acid, gradually eliminates the substituent on the nitrogen atom of benzimidazole ring and affords a sustained acid secretion-suppressive action. Further studies based on these findings have resulted in the completion of the present invention.
  • 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole is modified to give a prodrug (the compound of the formula (I)) stable to acid, which enables oral administration of the compound as a conventional tablet and the like without formulating an enteric-coated preparation.
  • a prodrug the compound of the formula (I)
  • the cost for formulating an enteric-coated preparation can be eliminated and the preparation of tablet and the like can be made smaller.
  • a smaller preparation is advantageous in that it is easily swallowed by patients having difficulty in swallowing, particularly the elderly and children.
  • the present invention provides the following.
  • the "C 6-14 aryl group” is a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples thereof include phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl. Preferred is an aromatic hydrocarbon group having 6 to 10 carbon atoms, and for R, phenyl is particularly preferable.
  • the "halogen” is fluorine, chlorine, bromine or iodine.
  • the halogen as a substituent of the hydrocarbon group represented by R and alkylidene group for A in the formula (I) is preferably fluorine or chlorine.
  • the "C 1-6 alkoxy group optionally substituted by halogen” is a linear or branched chain alkoxy group having 1 to 6 carbon atoms, which is optionally substituted by halogen (as defined above, preferably 1 to 5, more preferably 1 to 3, halogens).
  • halogen as defined above, preferably 1 to 5, more preferably 1 to 3, halogens.
  • Examples of the C 1-6 alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, with preference given to an alkoxy group having 1 to 4 carbon atoms.
  • halogen as the C 1-6 alkoxy group optionally substituted by halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy are preferable.
  • the "C 1-6 alkyl group” means a linear or branched chain alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl and the like, with preference given to alkyl group having 1 to 4 carbon atoms.
  • R ethyl, isopropyl and tert-butyl are preferable, and isopropyl is particularly preferable.
  • the "C 7-12 aralkyloxy group” is an aralkyloxy group having 7 to 12 carbon atoms, wherein the aryl group is as defined for the above-mentioned aryl group (preferably phenyl group) and the alkyl moiety is as defined for the above-mentioned "C 1-6 alkyl group". Examples thereof include benzyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy and the like. Preferred is an aralkyloxy group having 7 to 11 carbon atoms, and particularly preferred is benzyloxy.
  • the "C 1-5 alkoxy-carbonyl group” is an alkoxycarbonyl group wherein the alkoxy moiety is a linear or branched chain alkoxy group having 1 to 5 carbon atoms, which is exemplified by methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and the like.
  • Preferred is an alkoxycarbonyl group wherein the alkoxy moiety has 1 to 4 carbon atoms, and particularly preferred are methoxycarbonyl and ethoxycarbonyl.
  • the "C 1-6 alkyl group optionally substituted by halogen” is a C 1-6 alkyl group (as defined above) optionally substituted by halogen (as defined above, preferably 1 to 5, more preferably 1 to 3, halogens), which is preferably methyl, ethyl, propyl, isopropyl or trifluoromethyl.
  • alkylidene group having 2 or more carbon atoms in the present invention is a linear or branched chain alkylidene group having 2 or more carbon atoms, which is, for example, ethylidene, propylidene, butylidene, pentylidene or hexylidene, preferably an alkylidene group having 2 to 6 carbon atoms, more preferably a linear alkylidene group having 2 or 3 carbon atoms.
  • ethylidene and propylidene are preferable, and ethylidene is particularly preferable.
  • the "C 2-6 alkenyl group” is a linear or branched chain alkenyl group having 2 to 6 carbon atoms, which is exemplified by vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, isopentenyl, neopentenyl, 1-methylpropenyl, n-hexenyl, isohexenyl, 1,1-dimethylbutenyl, 2,2-dimethylbutenyl, 3,3-dimethylbutenyl, 3,3-dimethylpropenyl, 2-ethylbutenyl and the like.
  • Preferred is an alkenyl group having 2 to 4 carbon atoms, and particularly preferred are vinyl, n-propenyl and isopropenyl.
  • the "C 2-6 alkynyl group” is a linear or branched chain alkynyl group having 2 to 6 carbon atoms, which is exemplified by ethynyl, n-propynyl (1-propynyl), isopropynyl (2-propynyl), n-butynyl, isobutynyl, sec-butynyl, tert-butynyl, n-pentynyl, isopentynyl, neopentynyl, 1-methylpropynyl, n-hexynyl, isohexynyl, 1,1-dimethylbutynyl, 2,2-dimethylbutynyl, 3,3-dimethylbutynyl, 3,3-dimethylpropynyl, 2-ethylbutynyl and the like.
  • Preferred is an alkynyl group having 2 or 3 carbon atoms
  • the "C 3-8 cycloalkyl group” is a linear or branched chain cycloalkyl group having 3 to 8 carbon atoms, which is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Preferred is a cycloalkyl group having 5 to 7 carbon atoms, more preferred are cyclopentyl, cyclohexyl and cycloheptyl, and particularly preferred is cyclohexyl.
  • amino group optionally substituted by C 1-6 alkyl group in the present invention means an amino group optionally substituted by the "C 1-6 alkyl group” as defined above.
  • examples thereof include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino and the like, with preference given to methylamino, ethylamino, propylamino and isopropylamino.
  • the acyl group of the "acylamino group” in the present invention is preferably an alkanoyl group having 1 to 6, more preferably 1 to 3, carbon atoms.
  • acylamino group for example, formylamino, acetylamino, propionylamino and the like can be mentioned, with preference given to acetylamino.
  • the "hydrocarbon group” encompasses an aliphatic or aromatic hydrocarbon group, wherein the aliphatic hydrocarbon group means a saturated or unsaturated linear, branched chain or cyclic hydrocarbon group.
  • a hydrocarbon group having 1 to 14 carbon atoms is preferable, which is exemplified by a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group and a C 6-14 aryl group.
  • Preferred are a C 1-6 alkyl group, a C 3-8 cycloalkyl group and a C 6-14 aryl group and more preferred are a C 1-6 alkyl group and a C 3-8 cycloalkyl group.
  • the "metal cation" is exemplified by alkali metal ions (e.g., Na + , K + , Li + , Cs + etc.), with preference given to Na + and Cs + .
  • alkali metal ions e.g., Na + , K + , Li + , Cs + etc.
  • the "quaternary ammonium ion" is exemplified by tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium and the like, with particular preference given to tetrabutylammonium.
  • the "heterocyclic group” is a monovalent group, which is obtained by eliminating one optional hydrogen atom from a heterocycle having 1 to 3, preferably 1 or 2, hetero atoms (e.g., oxygen atom, nitrogen atom, sulfur atom, etc.) and may be saturated or unsaturated, and aromatic or aliphatic.
  • a and R in the formula (I) of the present invention may be bonded to each other to form a ring.
  • the ring is a 4- to 8-membered ring, preferably a 5- to 7-membered ring, which is a heterocycle containing at least one oxygen atom as a hetero atom (e.g., oxygen atom, nitrogen atom, sulfur atom etc.), and may be saturated or unsaturated.
  • a ring represented by the formula wherein the symbols in the formula are as defined above, can be mentioned.
  • the 4- to 8-membered ring formed by A and R bonded to each other is bonded to the N-position of the imidazole ring of the above-mentioned lansoprazole, and applied as a prodrug of a proton pomp inhibitor (PPI), or bonded to a different pyridylmethylsulfonyl substituted benzimidazole structure such as omeprazole, pantoprazole, rabeprazole and the like, and preferably applied as a prodrug of PPI.
  • PPI proton pomp inhibitor
  • Specific examples of the 4- to 8-membered ring formed by A and R of the formula (I) bonded to each other in the present invention include 1,3-dioxolan-2-one, dihydrofuran-2(3H)-one, 1,3-dioxan-2-one, tetrahydro-2H-pyran-2-one and the like, with preference given to 1,3-dioxolan-2-one.
  • the "hydrocarbon group" of the present invention may be substituted, wherein the substituent is exemplified by a C 6-14 aryl group, a hydroxy group, a halogen, a C 1-6 alkoxy group optionally substituted by halogen, a C 7-12 aralkyloxy group, a C 1-5 alkoxy-carbonyl group, a C 1-6 alkyl group optionally substituted by halogen, an acylamino group, an amino group optionally substituted by C 1-6 alkyl group and the like.
  • the number of the substituents is 1 to 5, preferably 1 to 3.
  • the "C 1-6 alkyl group”, “C 2-6 alkenyl group” and “C 2-6 alkynyl group” in the hydrocarbon group of the present invention may be substituted, and the preferable substituent is exemplified by (i) a C 6-14 aryl group, (ii) a hydroxy group, (iii) a halogen, (iv) a C 1-6 alkoxy group optionally substituted by halogen, (v) a C 7-12 aralkyloxy group, (vi) a C 1-5 alkoxy-carbonyl group, (vii) an acylamino group, (viii) an amino group optionally substituted by C 1-6 alkyl group and the like. Of these, (i) to (vii) are preferable, and (i) to (vi) are more preferable.
  • the number of the substituents is 1 to 5, preferably 1 to 3.
  • C 3-8 cycloalkyl group” and "C 6-14 aryl group” may be substituted, wherein the substituent is exemplified by (i) a C 6-14 aryl group, (ii) a hydroxy group, (iii) a halogen, (iv) a C 1-6 alkoxy group optionally substituted by halogen, (v) a C 7-12 aralkyloxy group, (vi) a C 1-5 alkoxy-carbonyl group, (vii) a C 1-6 alkyl group optionally substituted by halogen, (viii) an amino group optionally substituted by C 1-6 alkyl group and the like. Of these, (i) to (vii) are preferable.
  • the number of the substituent(s) is 1 to 5, preferably 1 to 3.
  • alkylidene group having 2 or more carbon atoms may be substituted, wherein the substituent is exemplified by a halogen, a C 1-6 alkoxy group (same as the "C 1-6 alkoxy group” of the above-mentioned "C 1-6 alkoxy group optionally substituted by halogen") and the like, with particular preference given to a halogen.
  • R in the formula (I) is preferably a C 1-6 alkyl group, a C 2-6 alkenyl group or a C 2-6 alkynyl group, which optionally has substituent(s) selected from the group consisting of (i) a C 6-14 aryl group, (ii) a hydroxy group, (iii) a halogen, (iv) a C 1-6 alkoxy group optionally substituted by halogen, (v) a C 7-12 aralkyloxy group, (vi) a C 1-5 alkoxy-carbonyl group and (vii) an acylamino group, or a C 3-8 cycloalkyl group or a C 6-14 aryl group, which optionally has substituent(s) selected from the group consisting of (i) a C 6-14 aryl group, (ii) a hydroxy group, (iii) a halogen, (iv) a C 1-6 alkoxy group optionally substituted by halogen
  • R in the formula (I) and R' in the formula (I') are more preferably a C 1-6 alkyl group, a C 2-6 alkenyl group or a C 2-6 alkynyl group, which optionally has substituent(s) selected from the group consisting of (i) a C 6-14 aryl group, (ii) a hydroxy group, (iii) a halogen, (iv) a C 1-6 alkoxy group optionally substituted by halogen, (v) a C 7-12 aralkyloxy group and (vi) a C 1-5 alkoxy-carbonyl group, or a C 3-8 cycloalkyl group or a C 6-14 aryl group, which optionally has substituent(s) selected from the group consisting of (i) a C 6-14 aryl group, (ii) a hydroxy group, (iii) a halogen, (iv) a C 1-6 alkoxy group optionally substituted by halogen
  • R in the formula (I) may be the hetero ring as mentioned above, and the hetero ring may have substituent(s).
  • substituents of the "hydrocarbon group” a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group and the like can be mentioned. Of these substituents, 1 to 5, preferably 1 to 3, may be used.
  • a C 2-6 alkylidene group optionally substituted by halogen is preferable, an ethylidene group and a propylidene group are more preferable, and an ethylidene group is particularly preferable.
  • a pharmacologically acceptable basic salt can be formed between an acidic group in a molecule and an inorganic base, an organic base and the like.
  • the basic salt is, for example, an inorganic basic salt (e.g., salt with alkali metal (e.g., sodium, potassium etc.), alkaline earth metal (e.g., calcium etc.), ammonia etc.), an organic basic salt (e.g., salt with dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, collidine etc.) and the like.
  • an inorganic basic salt e.g., salt with alkali metal (e.g., sodium, potassium etc.), alkaline earth metal (e.g., calcium etc.), ammonia etc.
  • an organic basic salt e.g., salt with dimethylamine, triethylamine, piperazine, pyrrol
  • a pharmacologically acceptable acid addition salt can be formed between a basic group in a molecule and an inorganic acid, an organic acid and the like.
  • the acid addition salt is, for example, an inorganic acid salt (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), an organic acid salt (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like.
  • an inorganic acid salt e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.
  • an organic acid salt e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesul
  • the compound (I) of the present invention encompasses hydrates.
  • examples of the "hydrate” include 0.5 hydrate - 5.0 hydrate. Of these, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate and 2.0 hydrate are preferable.
  • the compound (I) of the present invention encompasses racemates, optically active compounds and a mixture thereof.
  • optically active compound such compound wherein one enantiomer is in enantiomer excess (e.e.) of not less than 90% is preferable, more preferably in enantiomer excess (e.e.) of not less than 99%.
  • an optically active form an (R)-form represented by the formula wherein each symbol is as defined above, is preferable.
  • a and R in the formula (I) of the present invention the "A is an alkylidene group having 2 or more carbon atoms and optionally having substituent(s), R is a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s), or A and R may be bonded to each other to form a 4- to 8-membered ring optionally having substituent(s)" includes (i) an embodiment wherein A and R are bonded to each other to form a 4- to 8-membered ring optionally having substituent(s) and D is an oxygen atom or a bond, and (ii) an embodiment wherein A and R are not bonded to each other, A is an alkylidene group having 2 or more carbon atoms and optionally having substituent(s), and R is a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s).
  • the compound (I) can be produced by a method known per se, such as the methods described in US Patent Nos. 4,873,337 and 5,021,433, or a similar method, such as the following methods A and B.
  • compound (II) or a salt thereof is condensed with compound (III), whereby compound (I) or a salt thereof can be obtained.
  • M is a hydrogen atom, a metal cation or a quaternary ammonium ion
  • X is a leaving group, and other symbols are as defined above.
  • a halogen atom chlorine atom, bromine atom, fluorine atom, iodine atom
  • a C 1-6 alkylsulfonyloxy group e.g., methanesulfonyloxy, ethanesulfonyloxy etc.
  • a C 6-10 arylsulfonyloxy group e.g., benzenesulfonyloxy, p-toluenesulfonyloxy etc.
  • Method A is performed by reacting compound (II) or a salt thereof with compound (III) in the presence of a base.
  • a base is added to a mixed solution of compound (II) or a salt thereof and compound (III), and the mixture is stirred.
  • the salt of compound (II) here is exemplified by those similar to the above-mentioned salts of compound (I), which are acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.), and the like.
  • acid addition salts such as inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate
  • the reaction of Method A is generally conducted in a solvent, and a solvent that does not inhibit the above-mentioned reaction is selected as appropriate.
  • solvent include alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, tert-butanol etc.), ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether etc.), esters (e.g., ethyl formate, ethyl acetate, n-butyl acetate etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane etc.), hydrocarbons (e.g., n-hexane, benzene, tol
  • the base in Method A is, for example, an inorganic base such as C 1-6 alkyl lithium or C 6-10 aryl lithium (e.g., methyl lithium, ethyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, phenyl lithium etc.), lithium C 2-6 alkylamides (e.g., lithium dimethylamide, lithium diethylamide, lithium diisopropylamide etc.), metal hydrides (e.g., lithium hydride, sodium hydride etc.), alkali metal C 1-6 alkoxides (e.g., lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.), alkali metal amides (e.g., lithium amide, potassium amide, sodium amide etc.), alkali metal hydroxides (e.g., lithium hydroxide, potassium hydroxide, sodium hydroxide etc
  • the lower limit of the amount of the base to be used is generally not less than 0.1 mol, preferably not less than 0.5 mol, more preferably not less than 1 mol, and the upper limit is generally not more than 10 mol, preferably not more than 3 mol, relative to 1 mol of compound (II) or a salt thereof.
  • Method A generally 1 mol - 5 mol, preferably 1 mol - 3 mol, of compound (III) can be used per 1 mol of compound (II).
  • Method A is generally performed at a temperature of from about -80°C to 100°C, preferably 0°C to 60°C, depending on the kinds of compounds (II) and (III) and the solvent, reaction temperature and the like, and generally completes in 1 min.-72 hrs., preferably 15 min. - 24 hrs.
  • the compound (II) can be produced according to the method described in JP-A-61-50978, USP 4,628,098 and the like or a method similar thereto.
  • the compound (III) is produced according to the methods described in Journal of The American Chemical Society, vol. 43, p. 651 (1921), JP-B-61-40246, JP-B-4-58460 and Journal of The American Chemical Society, vol. 105, p. 7592 (1983) or a method analogous thereto.
  • the compound (I) or a salt thereof can be obtained by subjecting compound (IV) or a salt thereof to an oxidation reaction. wherein each symbol is as defined above.
  • the reaction in Method B can be carried out using an oxidant such as nitric acid, hydrogen peroxide, peroxy acid (e.g., magnesium monoperoxyphthalic acid etc.), peroxy acid ester, ozone, dinitrogen tetraoxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, tert-butyl hypochlorite, diazabicyclo[2.2.2]octane-bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cerium ammonium nitrate, bromine, chlorine, sulfuryl chloride, 3-chloroperoxybenzoic acid and the like.
  • an oxidant such as nitric acid, hydrogen peroxide, peroxy acid (e.g., magnesium monoperoxyphthalic acid etc.), peroxy acid ester, ozone, dinitrogen tetraoxide, iodosobenzene
  • the amount of the oxidant to be used is generally 0.5 mol - 2 mol, preferably 0.8 mol - 1.2 mol, per 1 mol of compound (IV) or a salt thereof.
  • a catalyst such as vanadium acetate and the like.
  • the reaction of Method B is generally carried out in a solvent inert to the above-mentioned oxidation reaction.
  • solvent inert to the above-mentioned oxidation reaction examples include water, alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol etc.), ketones (e.g., acetone, methyl ethyl ketone etc.), nitriles (e.g., acetonitrile, propionitrile etc.), amides (e.g., formamide, N,N-dimethylformamide etc.), ethers (e.g., diethyl ether, tert-butyl methyl ether, diisopropyl ether, dioxane, tetrahydrofuran etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), polar solvents (e.g., sulfolane, hexamethylphosphoric acid
  • the "solvent inert to the above-mentioned oxidation reaction” is used in an amount of generally not less than a 1-fold amount by weight of compound (IV) or a salt thereof for the lower limit, and generally not more than a 200-fold amount by weight of compound (IV) or a salt thereof, preferably not more than a 100-fold amount by weight of compound (IV) or a salt thereof for the upper limit.
  • Method B is generally carried out at a temperature of from -80°C to 80°C, preferably 0°C to 30°C and generally completes in 1 min. - 6 hrs., preferably 15 min. - 1 hr.
  • the compound (IV) which is a starting material of Method B, can be obtained by subjecting 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-benzimidazole to a reaction similar to the reaction in Method A.
  • the reaction may be carried out in the co-presence of a catalyst such as 18-crown-6.
  • the salt of compound (IV) is exemplified by the above-mentioned salts of the compound (I), which are acid addition salts such as inorganic acid salt (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like.
  • acid addition salts such as inorganic acid salt (e.g., hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-tol
  • the compound (I) and a salt thereof obtained by the above-mentioned methods A and B can be isolated and purified from the reaction mixture by a separation means known per se (e.g., concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography etc.).
  • a separation means known per se e.g., concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography etc.
  • (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole can be produced by, for example, (A) subjecting 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole or a salt thereof to optical resolution, (B) asymmetric oxidation of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-benzimidazole or (C) the production method described in WO00/78745, WO01/83473 and the like, and the like.
  • the method of optical resolution of (A) includes methods known per se, such as fractional recrystallization methods, chiral column methods, diastereomer methods, and so forth.
  • Asymmetric oxidation of (B) includes methods known per se, such as the method described in WO96/02535 and the like.
  • the “fractional recrystallization method” includes a method in which a salt is formed between a racemate and an optically active compound [e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine etc.], which salt is separated by fractional recrystallization etc. and, if desired, subjected to a neutralization process to give a free optical isomer.
  • an optically active compound e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine etc.
  • the "chiral column method” includes a method in which a racemate or a salt thereof is applied to a column for optical isomer separation (chiral column).
  • a chiral column such as ENANTIO-OVM (produced by Tosoh Corporation), the CHIRAL series (produced by Daicel Corporation) and the like, and developing the racemate in water, a buffer (e.g., phosphate buffer), an organic solvent (e.g., hexane, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, triethylamine etc.), or a solvent mixture thereof.
  • a chiral column such as CP-Chirasil-DeX CB (produced by GL Science) and the like is used to separate optical isomers.
  • the "diastereomer method” includes a method in which a racemate and an optically active reagent are reacted (preferably, an optically active reagent is reacted with the group at the 1-position of the benzimidazole group) to give a diastereomeric mixture, which is then subjected to ordinary separation means (e.g., fractional recrystallization, chromatography etc.) to obtain either diastereomer, which is subjected to a chemical reaction (e.g., acid hydrolysis, base hydrolysis, hydrogenolysis etc.) to cut off the optically active reagent moiety, whereby the desired optically active compound is obtained.
  • a chemical reaction e.g., acid hydrolysis, base hydrolysis, hydrogenolysis etc.
  • Said "optically active reagent” includes, for example, optically active organic acids such as MTPA [ ⁇ -methoxy- ⁇ -(trifluoromethyl)phenylacetic acid], (-)-menthoxyacetic acid and the like, optically active alkoxymethyl halides such as (1R-endo)-2-(chloromethoxy)-1,3,3-trimethylbicyclo[2.2.1]heptane and the like, and the like.
  • the compound (I) and a salt thereof of the present invention may be racemates or optically active compounds. They are particularly preferably in an (R)-form.
  • the compound (I) and a salt thereof of the present invention are converted to 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (hereinafter sometimes to be referred to as lansoprazole), which is a conventionally known proton pump inhibitor, in living organisms, and are useful as pharmaceutical agents, because they have a superior anti-ulcer activity, a gastric acid secretion-suppressive action, a mucosa-protecting action, an anti- Helicobacter pylori action and the like, and show low toxicity.
  • lansoprazole is a conventionally known proton pump inhibitor, in living organisms, and are useful as pharmaceutical agents, because they have a superior anti-ulcer activity, a gastric acid secretion-suppressive action, a mucosa-protecting action, an anti- Helicobacter pylori action and the like, and show low
  • enteric-coated preparations since they are stable to acid, they do not require formulation into an enteric-coated preparation for oral administration, which in turn eliminates the cost for formulating enteric-coated preparation.
  • the tablet can be made smaller, which is easily swallowed by patients having difficulty in swallowing, particularly the elderly and children.
  • absorption is faster than in enteric-coated preparations, expression of gastric acid secretion-suppressive action is rapid.
  • the preparation is long-acting because it is gradually converted to a conventionally known proton pump inhibitor in living organisms. Consequently, the compounds are useful as anti-ulcer agents and the like.
  • the compound (I) and a salt thereof of the present invention are useful for the prophylaxis or treatment of peptic ulcer (e.g., gastric ulcer, gastric ulcer due to post-operative stress, duodenal ulcer, anastomotic ulcer, Zollinger-Ellison syndrome, ulcer caused by nonsteroidal antiinflammatory etc.); gastritis; reflux esophagitis; symptomatic gastroesophageal reflux disease (symptomatic GERD); NUD (Non Ulcer Dyspepsia); gastric cancer (including gastric cancer due to promoted production of interleukin-1 ⁇ caused by genetic polymorphism of interleukin-1); gastric MALT lymphoma; Zollinger-Ellison syndrome; gastric hyperacidity (e.g.
  • gastric hyperacidity due to post-operative stress gastric hyperacidity due to post-operative stress
  • hemorrhage of upper gastrointestinal tract caused by acute stress ulcer, hemorrhagic gastritis, invasion stress (stress due to major surgery requiring intensive management after operation and cerebrovascular disorder, external injury in the head, multiple organ failure and extensive burn requiring intensive treatment) etc., and the like, pre-anesthetic administration, eradication of Helicobacter pylori , and the like, in mammals (e.g., human, simian, sheep, cattle, horse, dog, cat, rabbit, rat, mouse etc.).
  • mammals e.g., human, simian, sheep, cattle, horse, dog, cat, rabbit, rat, mouse etc.
  • the content of compound (I) or a salt thereof of the present invention in the pharmaceutical composition of the present invention is about 0.01 to 100% by weight relative to the entire composition.
  • its dose is about 0.5 to 1,500 mg/day, preferably about 5 to 150 mg/day, based on the active ingredient, when, for example, the compound is orally administered as an anti-ulcer agent to an adult human (60 kg).
  • the compound (I) or a salt thereof of the present invention may be administered once daily or in 2 or 3 divided portions per day.
  • the compound (I) and a salt thereof of the present invention show low toxicity and can be safely administered orally or parenterally (e.g., topical, rectal, intravenous administrations etc.) as they are or as a preparation containing a pharmaceutical composition containing a pharmacologically acceptable carrier admixed according to a method known per se, such as tablets (including sugar-coated tablets and film-coated tablets), powder, granule, capsule (including soft capsule), orally disintegrating tablet, liquid, injection, suppository, sustained-release preparation, plaster and the like. Particularly, they are preferably administered as oral agents in the form of tablet, granules, capsule and the like.
  • the pharmacologically acceptable carrier that may be used to produce the pharmaceutical composition of the present invention includes various organic or inorganic carrier substances in common use as pharmaceutical materials, including excipients, lubricants, binders, disintegrants, water-soluble polymers and basic inorganic salts for solid preparations; and solvents, dissolution aids, suspending agents, isotonizing agents, buffers and soothing agents for liquid preparations and the like.
  • Other ordinary additives such as preservatives, anti-oxidants, coloring agents, sweetening agents, souring agents, bubbling agents, flavors etc. may be also used as necessary.
  • excipients include, for example, lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride, titanium oxide and the like.
  • Such “lubricants” include, for example, magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc, stearic acid and the like.
  • binder include, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, low-substituted hydroxypropyl cellulose and the like.
  • Such “disintegrants” include (1) crosslinked povidone, (2) what is called super-disintegrants such as crosslinked carmellose sodium (FMC-Asahi Chemical) and carmellose calcium (Gotoku Yakuhin) etc., (3) carboxymethyl starch sodium (e.g., product of Matsutani Chemical), (4) low-substituted hydroxypropyl cellulose (e.g., product of Shin-Etsu Chemical), (5) corn starch, and so forth.
  • super-disintegrants such as crosslinked carmellose sodium (FMC-Asahi Chemical) and carmellose calcium (Gotoku Yakuhin) etc.
  • carboxymethyl starch sodium e.g., product of Matsutani Chemical
  • low-substituted hydroxypropyl cellulose e.g., product of Shin-Etsu Chemical
  • Said "crosslinked povidone” may be any crosslinked polymer having the chemical name 1-ethenyl-2-pyrrolidinone homopolymer, including polyvinylpolypyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer, and is exemplified by Colidon CL (produced by BASF), Polyplasdon XL (produced by ISP), Polyplasdon XL-10 (produced by ISP), Polyplasdon INF-10 (produced by ISP) and the like.
  • PVPP polyvinylpolypyrrolidone
  • Colidon CL produced by BASF
  • Polyplasdon XL produced by ISP
  • Polyplasdon XL-10 produced by ISP
  • Polyplasdon INF-10 produced by ISP
  • water-soluble polymers include, for example, ethanol-soluble water-soluble polymers [e.g., cellulose derivatives such as hydroxypropyl cellulose (hereinafter also referred to as HPC) etc., polyvinylpyrrolidone and the like], ethanol-insoluble water-soluble polymers [e.g., cellulose derivatives such as hydroxypropylmethyl cellulose (hereinafter also referred to as HPMC), methyl cellulose, carboxymethyl cellulose sodium etc., sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum etc.] and the like.
  • HPC hydroxypropyl cellulose
  • HPMC hydroxypropylmethyl cellulose
  • HPMC hydroxypropylmethyl cellulose
  • Such “basic inorganic salts” include, for example, basic inorganic salts of sodium, potassium, magnesium and/or calcium. Preferred are basic inorganic salts of magnesium and/or calcium. More preferred are basic inorganic salts of magnesium. Such basic inorganic salts of sodium include, for example, sodium carbonate, sodium hydrogen carbonate, disodium hydrogenphosphate and the like. Such basic inorganic salts of potassium include, for example, potassium carbonate, potassium hydrogen carbonate and the like.
  • Such basic inorganic salts of magnesium include, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg 6 Al 2 (OH) 16 ⁇ CO 3 ⁇ 4H 2 O] , and alumina hydroxide magnesium.
  • Preferred are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like.
  • Such basic inorganic salts of calcium include, for example, precipitated calcium carbonate, calcium hydroxide, and the like.
  • solvents include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • dissolution aids include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • Such “suspending agents” include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, monostearic glycerol etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose etc., and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, monostearic glycerol etc.
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl
  • Such “isotonizing agents” include, for example, glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol and the like.
  • buffers include, for example, buffer solutions of phosphates, acetates, carbonates, citrates etc., and the like.
  • Such “soothing agents” include, for example, benzyl alcohol and the like.
  • Such “preservatives” include, for example, p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidants include, for example, sulfites, ascorbic acid, ⁇ -tocopherol and the like.
  • Such “coloring agents” include, for example, food colors such as Food Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 etc.; food lake colors, red oxide and the like.
  • sweetening agents include, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.
  • Such “souring agents” include, for example, citric acid (citric anhydride), tartaric acid, malic acid and the like.
  • Such “bubbling agents” include, for example, sodium bicarbonate and the like.
  • Such “flavors” may be synthetic substances or naturally occurring substances, and include, for example, lemon, lime, orange, menthol, strawberry and the like.
  • the compound of the present invention may be prepared as a preparation for oral administration in accordance with a commonly-known method, by, for example, compression-shaping in the presence of a carrier such as an excipient, a disintegrant, a binder, a lubricant, or the like, and subsequently coating the preparation as necessary by a commonly known method for the purpose of taste masking, enteric dissolution or sustained release.
  • a carrier such as an excipient, a disintegrant, a binder, a lubricant, or the like
  • an intermediate layer may be provided by a commonly known method between the enteric layer and the drug-containing layer for the purpose of separation of the two layers.
  • available methods include, for example, a method in which a core containing crystalline cellulose and lactose is coated with the compound (I) or a salt thereof of the present invention and, where necessary, a basic inorganic salt, and then further coated with a coating layer containing a water-soluble polymer to give a composition, which is coated with an enteric coating layer containing polyethylene glycol, further coated with an enteric coating layer containing triethyl citrate, still further coated with an enteric coating layer containing polyethylene glycol, and finally coated with mannitol to give fine granules, which are mixed with additives and shaped.
  • enteric coating layer includes, for example, a layer consisting of a mixture of one or more kinds from aqueous enteric polymer substrates such as cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methacrylic acid copolymers (e.g., Eudragit L30D-55 (trade name; produced by Rohm), Colicoat MAE30DP (trade name; produced by BASF), Polyquid PA30 (trade name; produced by Sanyo Chemical) etc.), carboxymethylethyl cellulose, shellac and the like; sustained-release substrates such as methacrylic acid copolymers (e.g., Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name) etc.) and the like; water-soluble polymers; plasticizers such as triethyl citrate, polyethylene glycol, acetylated
  • additive includes, for example, water-soluble sugar alcohols (e.g., sorbitol, mannitol, maltitol, reduced starch saccharides, xylitol, reduced palatinose, erythritol etc.), crystalline cellulose (e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose carmellose sodium) etc.), low-substituted hydroxypropyl cellulose (e.g., LH-22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical), mixtures thereof etc.) and the like.
  • binders, souring agents, bubbling agents, sweetening agents, flavors, lubricants, coloring agents, stabilizers, excipients, disintegrants etc. are also used.
  • the compound of the present invention may be further used in combination with 1 to 3 other active ingredients.
  • Such “other active ingredients” include, for example, anti- Helicobacter pylori active substances, imidazole compounds, bismuth salts, quinolone compounds, and so forth.
  • antibiotic penicillins e.g., amoxicillin, benzylpenicillin, piperacillin, mecillinam etc.
  • antibiotic cefems e.g., cefixime, cefaclor etc.
  • antibiotic macrolides e.g., erythromycin, clarithromycin etc.
  • antibiotic tetracyclines e.g., tetracycline, minocycline, streptomycin etc.
  • antibiotic aminoglycosides e.g., gentamicin, amikacin etc.
  • imidazole compounds include, for example, metronidazole, miconazole and the like.
  • bismuth salts include, for example, bismuth acetate, bismuth citrate and the like.
  • quinolone compounds include, for example, ofloxacin, ciploxacin and the like.
  • a combination therapy of compound (I) or a salt thereof of the present invention with antibiotic penicillin e.g., amoxicillin etc.
  • antibiotic erythromycin e.g., clarithromycin etc.
  • Such “other active ingredients” and the compound (I) or a salt thereof of the present invention may be mixed, prepared as a single pharmaceutical composition [e.g., tablets, powders, granules, capsules (including soft capsules), liquids, injectable preparations, suppositories, sustained-release preparations etc.] in accordance with a commonly known method, and used in combination, and may also be prepared as separate preparations and administered to the same subject simultaneously or at a time interval.
  • a single pharmaceutical composition e.g., tablets, powders, granules, capsules (including soft capsules), liquids, injectable preparations, suppositories, sustained-release preparations etc.
  • room temperature indicates about 15 to 30°C.
  • Optical rotation [ ⁇ ] D was determined at 20°C, using the DIP-370 Digital polarimeter (produced by JASCO).
  • Diisopropylethylamine (0.733 L, 4.44 mol) was added to the obtained mixture at room temperature under a nitrogen stream, and cumene hydroperoxide (6.88 L, content 82%, 37.5 mol) was added at -5°C to 5°C. The mixture was stirred at -5°C to 5°C for 1.5 hrs. 30% Aqueous sodium thiosulfate solution (17 L) was added to the reaction mixture under a nitrogen stream, and the remaining cumene hydroperoxide was decomposed. After partitioning, water (4.5 L), heptane (13.5 L), t-butyl methyl ether (18 L) and heptane (27 L) were added successively to the obtained organic layer, and crystals were precipitated under stirring.
  • a suspension of the wet crystals in acetone (20 L) was added dropwise with stirring to a mixture of acetone (7 L) and water (34 L), and water (47 L) was added.
  • the wet crystals were dissolved in ethyl acetate (45 L) and water (3 L), and the mixture was partitioned.
  • the trace amount of the insoluble material in the organic layer was filtered off, and triethylamine (0.2 L) was added.
  • the mixture was concentrated under reduced pressure until the liquid amount became about 7 L.
  • Methanol (2.3 L) ca. 12.5% aqueous ammonia (23 L, ca. 50°C) and t-butyl methyl ether (22 L, ca. 50°C) were added to the concentrate, and the mixture was partitioned.
  • To the organic layer was added ca. 12.5% aqueous ammonia (11 L), and the mixture was partitioned (this step was repeated once).
  • the aqueous layers were combined, and ethyl acetate (22 L) was added.
  • Acetic acid was added dropwise under cooling, and pH was adjusted to about 8.
  • reaction solution was extracted with ethyl acetate - water, and the organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography (eluted with ethyl acetate) and crystallized from diisopropyl ether to give a less polar diastereomer (0.25 g) of the title compound as a colorless solid.
  • reaction solution was extracted with ethyl acetate - water, and the organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography (eluted with ethyl acetate) and recrystallized from ethyl acetate - diisopropyl ether to give a less polar diastereomer (0.85 g) of the title compound as a colorless solid.
  • reaction solution was extracted with ethyl acetate - water, and the organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography (eluted with ethyl acetate), and recrystallized from ethyl acetate - diisopropyl ether to give a less polar diastereomer (0.48 g) of the title compound as a colorless solid.
  • reaction solution was extracted with ethyl acetate - water, and the organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography (eluted with ethyl acetate) and recrystallized from ethyl acetate-diisopropyl ether to give a less polar diastereomer (0.90 g) of the title compound as a colorless solid.
  • reaction solution was extracted with ethyl acetate - water, and the organic layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the ethyl acetate layer was washed with aqueous sodium hydrogen carbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction solution was added to ethyl acetate (1.5 L) and the mixture was washed successively with 100 mM phosphate buffer, 10% aqueous sodium thiosulfate solution and saturated brine. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residual solid was washed with diethyl ether and dried under reduced pressure. The obtained solid was recrystallized from acetone to give a less polar diastereomer (18.0 g) of the title compound as a colorless solid.
  • reaction solution was extracted with ethyl acetate - water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (eluted with ethyl acetate), and recrystallized from ethyl acetate to give a less polar diastereomer (racemate, 860 mg) of the title compound as a colorless solid.
  • the compound of the present invention is converted to lansoprazole, which is a proton pump inhibitor, in living organisms and shows a superior anti-ulcer activity, a gastric acid secretion-suppressive action, a mucosa-protecting action, an anti-Helicobacter pylori action and the like.
  • the compound shows low toxicity and is useful as a pharmaceutical product.
  • the compound since the compound is stable to acid, it does not need to be formulated into an enteric-coated preparation, thereby eliminating the cost for formulating enteric-coated preparation.
  • the tablet becomes small it is easy to take for patients with weak swallowing capability, particularly the elderly and children.

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CN102399212B (zh) * 2010-08-23 2014-07-16 江苏豪森医药集团有限公司 一种右兰索拉唑晶型及其制备方法

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